Aliphatic mercurated alkyl amide



Patented June 20, 1939 UNETED STATES @FFEQE Donalee L. Tabern, LakeBlufi, Ill., assignor to Abbott Laboratories, NorthpChic ago, 111., acorporation of Illinois N Drawing. Application February 8, 1935,

Serial 8 Claims.

It is known that certain types of mercury compounds, in which themercury is attached to either an inorganic or organic radical, have thetherapeutic property of producing diuresis.

However, inorganic compounds of mercury are highly toxic and the ratiobetween the efiective diuretic dose and the toxic dose is such as topreclude their effective therapeutic use. The same diificulty exists inthe case of most organic in compounds of mercury, which are eithertoolow in therapeutic effectiveness or too high in toxicity to bedesirable.

I have discovered that mercuryderivatives of the unsaturated alkylamides of aliphatic acids,

1.) especially those containing one or more hydroxyl A OB (P i Q (R R)zin which a: is a'whole number, R and R are hydrogen orhydroxyl groups ortaken. together,

an oxygen atom, A and B are hydrogen or hydroxyl groups or takentogether, an oxygen atom, Q is hydrogen, hydroxyl, an alkylene amide orureide group or an alkylene amide or ureide group 40 to which has beenadded mercuric hydroxide or anorganic mercury salt, such as and D is analkylene amide or ureide group to which has been addedmercuric hydroxideor an organic mercury salt as above defined.

The composition of the final products of mercuration depends largely onthe methods employed. Simple evaporation or precipitation leads incertain cases to the retention of both acetoxy groups from the mercuricacetate; with more complex manipulation and intensive drying, hydrolysisand replacement of the acetoxy groups by hydroxyl and ultimatelyanhydride formation occur.

EXAMPLE 1 M ermtry derivatives of the dimllylamide) of saccharz'c acid15 grams of potassium acid saccharate is suspended in cc. absolutealcohol and dry 1101 passed in. When separation of the K01 is complete,it is filtered off and more HCl passed in. The solvent and hydrogenchloride are evaporated in vacuo. To the residual saccharic ester isadded 10 cc. allylamine; a vigorous reaction ensues and the solid allylamide of saccharic acid separates. It is recrystallized from methylalcohol. Six grams of this amide is dissolved in methyl alcohol, and asolution of six grams mercuric acetate in methyl alcohol is added. Thesolvent is removed and ether added to the residue, which causes a gummyprecipitate to form. This is dissolved in absolute ethyl alcohol andpoured into a large volume of ether. The precipitate has the probableformula:

The product is soluble in alcohol and water. The addition of hydrogensulfide gives a white or yellowish precipitate, later changing to black.

Mercuration may be also carried out in aqueous solution by simply mixingthe components in approximately equimo lecular (proportions, followed byfiltration, if necessary, and dilution to requisite volume.

EXAMPLE 2 Mercury derivative of the di(allylamide) of saccharzc acid Thedi(allylamide) of saccharic acid is treated with two molecularequivalents of mercuric acetate, by the method described in Example 1.This grams mercuric acetate added. The gummy pre-,

cipitate so formed is dissolved in dilute ammonium hydroxide solutionand dilute acetic acid added. Crystals of the mono-mercurated compoundslowly form. They have the probable formula:

25 COOH l CONHCHzCHGHzOH 30 EXAMPLE 4.-

Mercury derivative of the di(allylamide) of mucic acid This compound ofmucic acid may be prepared 35 by warming 2.9 grams of di(allylamide) ofmucic acid with 3.1 grams of mercuric acetate until solution occurs. Thesolvent is evaporated and ether added, which is evaporated in vacuo,leaving a friable solid mass. This monomercurateddi(ally1amide) of mucicacid is soluble in Water and alcohol. The probable formula is asfollows:

HHH

| O HgOH EXAMPLE 5 50 Mercury derivative of the di(allylamidc) of mucicacid Three grams of the di(allylamide) of mucic acid is caused to reactin hot methyl alcohol solution with six grams of mercuric acetate. Thesolution is evaporated to dryness, leaving the dimercurated compound asa friable mass. The product is soluble in water and alcohol. Theprobable formula is:

H I II I I O(lJ 0H HgOH (oHoHh 2 H 60 H NHc-oomo11 HgOlI EXAMPLE 6 70Mercury derivative 0 the di(aZlyZami-de) of tartaric'acid Thedi(e.llylamide) of tartaric acid is treated in methyl alcohol with onemolecular equivalent of mercuric acetate, the solvent is removed, andether is added. The mercurated compound is obtained as a semi-solid oilwhich, upon drying, yields a brittle, hygroscopic solid. It is solublein water. Hydrogen sulfide does not at once precipitate mercury sulfidefrom an aqueous solution of the product. The probable formula is:

CONHCHzOHCHzOCOCHa HgOH (OHOIEDi C0NHCH2CH=CH2 EXAMPLE 7 Mercuryderivative of the di(allylamide) of tartaric acid The use of twomolecular equivalents of mercuric acetate in the reaction described inExample 6, yields the di-mercurated product, having the probableformula:

CONHCH2-CHCH2OCOCHa With hydrogen sulfide, it at once yields a yellowprecipitate.

EXAMPLE 8 Mercury derivative of the di(/3-methylallylamide) of tartaricacid Ethyl tartrate is allowed to react in water or methyl alcohol withtwo molecular equivalents of c-methyl allylamine. This yields thecorresponding di-amide, as large white crystalline plates, melting at144-147 C. Reaction of this amide with one molecular equivalent ofmercuric acetate yields the mercurated compound, having the probablestructure:

Mercury derivative of the di(allylamide) of malic acid 5.2 grams of thedi(allylamide) of malic acid (plates, melting point 1489) and 8 grams ofmercuric acetate are mixed in methyl alcohol. The mass may not solidifydirectly on evaporation; hence, it is redissolved in alcohol and pouredinto ether. The product, analyzing for Hg(OI-I)2 addition, is a granularmass, sintering (forming a rock-like mass) on standing. The probableformula is:

(CHOH)2 C ONHCH2CHCH2OH r roon HgOH HCOH CONHCaHB EXAMPLE 10 Mercuryderivative of the allyl amide of glucomc acid grams of gluconic lactoneis shaken with.

10 cc. mono-allylamine in 60 cc. of absolute alcohol. The crystallineamide soon separates in excellent yield.

12 grams of this allylamide and 16 grams of mercuric acetate isdissolved in methyl alcohol. On evaporation, a hygroscopic glass-likemass results which is dried in a high vacuum at 50. The analysiscorresponds to the simple addition of mercuric acetate. The product issoluble in water, giving a stable colorless solution. Sodium hydroxidedoes not cause precipitation; hydrogen sulfide gives a yellowprecipitate, turning black on standing. It is a powerful diuretic indogs in doses as low as 1 mg. per kg. Probable formula is:

CHzOH(CHOH) CONHCHzOHOHzOCOCHa Hgooooru.

EXAMPLE 11 Mercury derivative of the allyl amide of levalinic acid Theallylamide of levulinic acid prepared from levulinic ethyl ester andallylamine is obtained as a viscous liquid. Mercuration with mercuricacetate yields the corresponding mercurated levulinic allylamide, whichis relatively unstable, splitting off metallic mercury in solution.Probable formula:

EXAMPLE 12 Mercury derivative of the allylamide of yalactom'c acidGalactonic allylamide is prepared as is the case of the gluoonicderivative, and melts at ISO-183 C.

12 grams of this amide and 16 grams of mercuric acetate are dissolved inmethyl alcohol and the solution concentrated. The addition of absoluteether gives a precipitate which is separated. Hydrogen sulfide added toan aqueous solution gives a yellow solution, changing to black on theaddition of acid. Analysis shows the product to be the result of asimple addition of mercuric acetate. Probable formula is:

cmoH

(OHOH) EXAMPLE 13 Gluco'heptonic acid derivatives Glucoheptonic lactoneand allylamine react to yield the solid allylamide. When this is causedto react with mercuric acetate, as in Example 12, the mercuric acetateaddition product of the amide is obtained as a glass-like wax, which iscompletely soluble in water. Probable formula is:

i i it OONHCC\C 0110150 Hg OAC omoH OH EXAMPLE 14 Mercury derivative ofthe allylamide of e-hydronzybatyric acid Ethyl c-oxybutyrate is causedto react with allylamine to give the liquid allylamide. When mercuratedwith one molecular equivalent of mercuric acetate, there results aviscous oil, soluble in water and. yielding a stable solution. Probableformula is:

H o H H; H om-om-JLir-iL-cm on Hg 0A0 7 GAO EXAMPLE 15 I M ercaryderivative of the allyl ureide of gluconic acid 7 grams of the ally]ureide of gluconic acid (prepared from gluconic lactone and allyl urea)are mixed in methyl alcohol with 7 grams of mercuric acetate. A smallamount of white precipitate is filtered off and the residue evaporatedto remove most of the methyl alcohol and then diluted with water asdesired for administration. Probable formula is:

By similar reactions, the following mercurated compounds have also beenprepared:

Mercury derivative of the di(allylamide) of malonic acid Mercuryderivative of the di(allylamide) of tartronic acid Mercury derivative ofthe tri(allylamide) of citric acid Mercury derivative of thedi(allylamide) of trihydroxy glutaric acid Mercury derivative of thedi(allylamide) of acetonedicarboxylic acid Mercury derivative of themono(allylamide) of adipic acid Mercury derivative of the di(allylamide)of malic acid Mercury derivative of the di(allylamide) of fumaric acidMercury derivative of the di(allylamide) of succinic acid Mercuryderivative of the di(allylamide) of diacetyl tartaric acid Mercuryderivative of the di(allylamide) of methyl ether of malic acid Mercuryderivative of the di(allylamide) of l-malic acid Mercury derivative ofthe mono(allylamide) of glycolic acid Mercury derivative of themono(allylamide) of acetic acid Mercury derivative of themono(allylamide) of glyceric acid Mercury derivative of themono(al1y1amide) of Xylonic acid Mercury derivative of themono(allylamide) of lactic acid Mercury derivative gulonic acid I claimas my invention: 1. A compound having the following formula:

of the mon0(allylamide) of 2. A compound having the following formula:

R'NHCH2(|3H(|3H2 in which R. represents the acyl group of an aliphaticacid having at least one hydroxyl group and in which one of the Rs isselected from the group consisting of HgOH and HgOCOCHs and the other Ris selected from the group consisting of OH and OCOCHs.

3. A compound having the following formula:

in which R represents the acyl group of an aliphatic acid having aplurality of hydroxyl groups and in which one of the Rs is selected fromthe group consisting of HgOH and HgOCOCHs and the other R is selectedfrom the group consisting of OH and OCOCH3.

4. A compound having the following formula:

GONHOaHa in which R, represents an acyl group having at least onehydroxyl group, and in which one of the Rs is selected from the groupconsisting of HgOH and HgOCOCI-Ia and the other R is selected from thegroup consisting of OH and OCOCHs.

6. A mono-mercurated compound of the type described having diureticproperties consisting of the reaction product of mercury acetate anddi(allylamide) of saccharic acid, said compound having the followingformula:

CONHCsHfi -NHCH2(|JH(|1H2 in which R represents an acyl group ofsaccharic acid and in which one of the Rs is selected from the groupconsisting of HgOH and HgOCOCHs and the other R is selected from thegroup consisting of OH and OCOCHs.

7. A mono-mercurated compound of the type described having diureticproperties consisting of the reaction product of mercury acetate anddi(allylamide) of malic acid, said compound hav ing the followingformula:

in which R represents an acyl group of malic acid and in which one ofthe Rs is selected from the group consisting of HgOH and HgOCOCHa andthe other R. is selected from the group consisting of OH and OCOCH3.

8. A mono-mercurated compound of the type described having diureticproperties consisting of the reaction product of mercury acetate anddi(allylamide) of gluconic acid, said compound having the followingformula:

CONHCaHs in which R represents an acyl group of gluconic acid and inwhich one of the Rs is selected from the group consisting of HgOH andHgOCOCHs and the other R is selected from the group consisting of OH andOCOCHs.

DONALEE L. TABERN.

